VERU-111 modulates gut microbiota and offers an advantage in colorectal cancer therapeutics 2252990

Abstract Introduction The global burden of colorectal cancer (CRC) has risen, positioning it as the third most common cancer worldwide. Chemotherapies are known to disrupt the composition of gut microbiota (GM) and lead to long-term health consequences for patients. How chemotherapeutic agents alter GM is not well known. We have shown that VERU-111 suppresses CRC tumors by inducing apoptosis and targeting myeloid PD-L1 expression in an AOM/DSS-induced model of CRC. Methods This study aimed to assess changes in the GM following VERU-111 treatment. We used 16S rRNA gene amplicon sequencing as well as a metagenomic study from fecal samples of different experimental groups to evaluate the alteration of GM. We also used computational tools to predict the functional potential of microbial communities based on 16S rRNA gene sequencing data. Results The administration of VERU-111 led to a restructured microbial community characterized by increased alpha and beta diversity as compared to AOM/DSS alone. Further, VERU-111 treatment significantly increased Verrucomicrobiota compared to the AOM/DSS alone. Akkermansia muciniphila was also elevated following VERU-111 treatment, which coincides with the increased CD8+ T cell population as well as reduced PD-L1-expressing macrophages in the colon as compared to control. Moreover, the relative abundance of Ruminococcus was also diminished, which is negatively correlated with immune checkpoint blockade therapy, while Muribaculum was notably increased following VERU-111 administration. An elevated abundance of Turicibacter was detected in the VERU-111-treated group compared to the control, showing a correlation with apoptotic activity and aligning well with our in vivo observations. The metagenomic study indicated that the microbial shift by VERU-111 was associated with suppression of several cancer-related pathways. Conclusion These favorable shifts in gut microbiota suggest a therapeutic dimension of VERU-111 in treating CRC and emphasize the need for further mechanistic exploration. Funding Source NIAID R01 AI140405 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)